Photodynamic therapy is an experimental cancer treatment utilizing a systemically injected photosensitizing agent that localizes in tumors and is activated by selected wavelengths of light. When the drug is stimulated by light, local tissue destruction occurs. There is evidence that both direct cellular effects and vascular destruction are important in the therapeutic response and that the formation of toxic oxygen compounds may be involved in the mechanism of action. Injury to outer cell membranes, mitochondria, and nuclear vacuolization have been found in treated cells, but by themselves appear to be only sublethal and do not produce permanent tumor eradication. There is evidence that PDT has extensive effects on normal and tumor microvasculature and that these effects are important in the tumor destruction caused by this treatment. The mechanisms producing these changes have not been extensively investigated. The broad goals of this research are to determine how the target segments of the microvasculature are affected by PDT, (b) to establish the nature of the factors and mechanism of action that produce these effects, (c) to determine how these factors influence tumor destruction and (d) to establish how the factors can be controlled or modified to increase the efficacy and efficiency of photodynamic therapy. The experimental approach to this problem involves testing three major hypotheses. First, we hypothesize that PDT results in the release of toxic molecules (singlet O2) from blood components, from the perivascular tissues or the endothelium. These molecules attack lipid membranes, liberating arachidonic acid, and enhance the dominance of proaggretory-constrictor metabolites over antiaggretory-dilator metabolites (12,13). This would cause vasoconstriction and platlet thrombi producing a rapid decrease in blood flow during PDT. The second hypothesis is that PDT results in the release of singlet oxygen which produces a direct toxic effect on the blood vessel wall followed by platelet aggregation at the site of injury. This would result in a decrease in blood flow and long term stasis in the tumor vasculature as well as that of the normal tissue surrounding the tumor. A persistent decrease in blood flow would render these tissues hypoxic and eventually could result in cell death. Third, we suggest that regulating tissue factors such as oxygenation temperature, and local tissue parameters will influence tumor survival and enable us to optimize PDT effects.